1. Field of Invention
Chemical compounds, photochemotherapy, compounds having an enhanced combination of photosensitizing properties for use in photochemotherapy, selective photosensitizing agents.
2. Prior Art
Psoralens have been used for years as dermal photosensitizing agents, e.g., in the treatment of vitiligo. Their topical and/or oral application, followed by irradiation with light, results in stimulation of melanin, thus producing a tanning effect. They have accordingly also been used for such cosmetic purpose. More recently, psoralens have been found useful in the photochemotherapeutic treatment of psoriasis, in which case they are administered orally or topically to the subject, whose skin is subsequently exposed to controlled ultraviolet radiation, as in Psoralite (TM) apparatus. A high percentage of remissions of this disease have been effected in such manner.
The effectiveness of a psoralen for such uses and for such purpose has in the past been related to its ability to produce erythema upon the skin upon irradiation. Psoralens also have other uses, and their uses, as well as underlying rationale and theory, are partially elucidated in U.S. Pat. Nos. 4,124,598 and 4,130,568, and are otherwise well-known in the art from various preexisting publications.
Rather recently, it has been found that the erythema, produced upon the skin of a patient or animal upon irradiation with ultraviolet light "A" in a so-called PUVA evaluation or application, after administration of psoralen to the subject, is associated with the linear structure of psoralens. This makes it possible for psoralens to engage in photocycloaddition reactions with double bonds of pyrimidine bases of macromolecules, such as present in the complementary strands of DNA (deoxyribonucleic acid), in a manner such that two double bonds of the psoralen compound react so as to produce two (2) cycloadditions with two (2) separate molecules of the pyrimidine base, as present in the complementary strands of DNA, thereby forming an interstrand crosslinkage. Such interstrand crosslinkages occur in photoreactions between highly erythematic linear psoralens and DNA. On the other hand, some psoralens, because of their angular structure, can engage, for geometric reasons, only one of the two photoreactive sites, thus effecting a single cycloaddition to only one of the two complementary strands of DNA with consequent production of a monofunctional adduct. In other words, psoralen compounds in the photoreaction with DNA can form either or both of monofunctional and bifunctional adducts, and this capacity varies with the type of psoralen compound involved, some compounds forming essentially only monofunctional adducts, whereas other compounds form solely or a preponderance of bifunctional adducts or interstrand crosslinkages. The ability or capacity to form only monofunctional and not bifunctional adducts, or at least minimization of bifunctional cycloaddition or bifunctional adduct formation, is now considered desirable from the standpoint that the consequences deriving from bifunctional damage are considered to be more serious from a biological repair standpoint than the consequences deriving from monofunctional cycloaddition or adduct effects. This means that it is at least no longer considered necessary that a compound exhibit strong bifunctional effects, as evidenced by a high degree of erythema in usual test procedures, for it to be useful in photochemotherapy, but that it is even preferred for it to produce monofunctional adducts or a single cycloaddition without interstrand crosslinkage to DNA. Psoralen compounds which produce monofunctional adducts only, or at least in preponderance, have been found effective in the treatment of psoriasis and in producing other desirable effects, such as tanning, even though they do not cause interstrand crosslinkages and consequent erythema. Such unique properties therefore constitute desirable and much sought after criteria or desideratum in the evaluation of photosensitizing compounds but, as already stated, up until the present time such psoralen compounds as produce monofunctional DNA adducts have been angular in their nature, such as some isopsoralens (or angelicins). However, the compounds of the present invention, despite their linear structure, for unknown reasons, are characterized by inability to crosslink DNA molecules and cause erythema, while nevertheless possessing ability to cause DNA monoaddition and production of monofunctional adducts, a totally unpredictable combination of characteristics for linear psoralen compounds. Further, linear psoralens are also characterized by established and recognized reactivity with ribonucleic acids (RNA), and accordingly the new psoralen compounds find use in the study of secondary structures of nucleic acids, as inhibitors of RNA replication, and in the inactivation of viruses, as well as in the photochemotherapy of psoriasis and in suntanning, all important uses.
The standard tests and test procedures, and their significance, are fully elucidated in the following publications:
F. Dall'Acqua, S. Marciani, G. Rodighiero: Interstrand crosslinkages occurring in the photoreaction between psoralen and DNA. FEBS letters 9, 121 (1970); F. Dall'Acqua, S. Marciani, L. Ciavatta, G. Rodighiero: Formation of interstrand cross-linkings in the photoreactions between furocoumarins and DNA. Zeitschrift Naturforsch. 26b, 561 (1971); Baccichetti et al., Z. Naturforsch. 34c, 811-814 (1979); Bordin et al., Biochimica et Biophysica Acta 447, 249-259 (1976); Baccichetti et al., Experientia 35, 183 (1979); and see U.S. Pat. Nos. 4,124,598 and 4,130,568, as well as Hearst et al., Nucleic Acids Res. 1977, 4(5), 1339-1347; Isaacs et al., Biochemistry 1977, 16(6), 1058-1064; Shen et al., J. Mol. Biol. 1977, 116(4), 661-679; and Johnson et al., Science 1977, 197(4306), 906-908.
The unique linear psoralen compounds of the present invention then, which possess the characteristic, when employed in PUVA therapy, of forming only monofunctional adducts or essentially so, without concurrent interstrand DNA crosslinkages or erythema, thus finding employment and use in the foregoing manners, particularly in the photochemotherapy of tanning and psoriasis, should be welcome additions to the physicians' armamentarium of useful drugs.